Emerging Thrombotic Complications in Patients Undergoing Chimeric Antigen Receptor T Cell Therapies

Introduction. Chimeric antigen receptor (CAR)-T cell therapies are a promising treatment approach for hematologic malignancies. There are currently 5 FDA approved products on the market since 2017 and several others under clinical investigation. While effective, a key limitation of CAR-T cell therapies is their associated toxicities.

Methods. We performed a single-center, retrospective study of all adult patients who received inpatient CAR-T cells at the Indiana University Simon Cancer Center between July 2018 and July 2022 for R/R DLBCL or MM as standard-of-care or on a clinical trial. We analyzed the incidence of emerging and unusual complications that go beyond the standard paradigm of cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicty syndrome (ICANS). We collected clinical characteristics, pre-existing thrombosis risk factors, laboratory results, and outcomes through chart review. We used descriptive statistics to evaluate risk factors, incidence, management, and outcomes of thrombotic events by medical record review. Median follow up time was 300 days.

Results. Sixty-nine patients who underwent CAR-T were included in the analysis, 46 with DLBCL and 23 with MM. For DLBCL, the mean age was 52.65 (range 20-76), and 37% were women. For MM, the mean age was 61.21 (range 48-81), and 35% were women. Patients with DLBCL received either Tisagenlecleucel (15, 32.6%) or Axicabtagene ciloleucel (31, 67.4%) and patients with MM received either Idecabtagene vicleucel (14, 60.9%) or Ciltacabtagene autoleucel (9, 39.1%).

Of these patients, 21.7% of DLBCL patients and 17.4% of MM patients had a history of venous thromboembolism (VTE), while 54.3% of DLBCL patients and 39.1% of MM patients had BMI ≥30.We identified that 50% of DLBCL and 26% of MM patients had ICANS of any grade and 82.6% of both DLBCL and MM patients had CRS of any grade.

A total of 7 (10.1%) patients developed thrombotic events post CAR-T therapy, out of which 6 were venous and 1 was arterial. All cases of thrombosis resolved with treatment, with the arterial case receiving therapy for an NSTEMI. Regarding the 6 VTE cases 5 were treated with direct oral anticoagulants (DOACs) and 1 with Low Molecular Weight Heparin (LMWH). There was no association between development of a thrombotic event and death. Median time to thrombosis was 13 days (range 3 to 113 days). 3 patients had a lower extremity DVT, 2 had PE and 1 had a CNS thrombosis. Per institutional protocol and due to concerns of thrombocytopenia, none of the patients in our cohort received VTE prophylaxis while hospitalized.

We analyzed several potential risk factors to predict development of thrombosis including coagulation and inflammatory markers, the development of CRS and ICANS, and the use of the ISTH DIC score and the Padua Score. There was no relation between development of a thrombotic event and the diagnosis, age, gender, prior history of VTE, obesity, Padua Score, CRS or peak ferritin. We did find a significant association between the development of ICANS (p=0.01) and an ISTH DIC Score ≥5 (p=0.04) with thrombosis.

Discussion. We report the emergent occurrence of rare thrombotic complications in adult patients with R/R DLBCL and MM receiving CD19 or BCMA directed CAR-T Cell therapies with an approximate rate of 10%. We observed that the ICANS grade and an ISTH DIC Score ≥5 was significantly associated with the development of these underappreciated complications. From this small case series, DOACs appeared an effective therapy to approach these this serious complication. These findings should be corroborated in larger prospective trials and efforts should be made for the implementation of risk adapted prophylactic strategies in patients undergoing CAR T-cell therapies.

Abu Zaid:Ossium Health: Consultancy; Pieris: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding; Janssen: Research Funding; Genentech: Research Funding; BMS: Research Funding; Cormedix: Current equity holder in publicly-traded company. Perna:Lonza: Research Funding; NGMBio: Research Funding.